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United States Patent |
5,599,534
|
Himmelstein
,   et al.
|
February 4, 1997
|
Reversible gel-forming composition for sustained delivery of
bio-affecting substances, and method of use
Abstract
Reversibly gel-forming compositions for sustained delivery of bio-affecting
substances are disclosed. The compositions exhibit significant changes in
viscosity in response to changes in pH. The compositions contain
relatively low concentrations of a stable combination of at least one
pH-responsive gelling polymer and at least one other thermally
nonresponsive polymer. The compositions are preferably formulated to
include one or more therapeutic or diagnostic agents for administration as
a liquid that will gel in situ or for topical application as a pre-formed
gel.
Inventors:
|
Himmelstein; Kenneth J. (Omaha, NE);
Baustian; Cara L. (Pearl River, NY)
|
Assignee:
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University of Nebraska (Omaha, NE)
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Appl. No.:
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287694 |
Filed:
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August 9, 1994 |
Current U.S. Class: |
424/78.04; 424/427; 424/428; 514/912; 514/913; 514/914; 514/915 |
Intern'l Class: |
A61K 031/74; A61K 031/19; A61K 047/38; A01N 025/04 |
Field of Search: |
424/78.04,427,428
514/912,913,914,915
|
References Cited
U.S. Patent Documents
4188373 | Feb., 1980 | Krezanoski et al. | 514/11.
|
4271143 | Jun., 1981 | Schoenwald et al. | 514/9.
|
4407792 | Oct., 1983 | Schoenwald et al. | 514/397.
|
4474751 | Oct., 1984 | Haslam et al. | 514/11.
|
4474752 | Oct., 1984 | Haslam et al. | 434/78.
|
4474753 | Oct., 1984 | Haslam et al. | 424/78.
|
5252318 | Oct., 1993 | Joshi et al. | 424/78.
|
5292516 | Mar., 1994 | Viegas et al. | 424/423.
|
5292517 | Mar., 1994 | Chang et al. | 424/426.
|
Other References
Podder et al., (1992), Exp. Eye Res., 54: 747-757.
Schoenwald et al., (1978) J. Pharm. Sci., 67: 1280-1283.
|
Primary Examiner: Azpuru; Carlos
Attorney, Agent or Firm: Dann, Dorfman, Herrell and Skillman
Claims
What is claimed is:
1. A reversibly gelling composition for sustained delivery of a therapeutic
or diagnostic agent, said composition exhibiting a reversible increase in
viscosity in response to variation in pH over a pre-determined range, said
composition comprising an aqueous solution including about 0.01% to 10.0%
(w/w) of at least one pharmaceutically acceptable pH-responsive gelling
polymer and about 0.01% to 20.0% (w/w) of at least one other
pharmaceutically acceptable thermally nonresponsive polymer.
2. The composition of claim 1, which exhibits a reversible increase in
viscosity in response to increasing pH.
3. The composition of claim 2, wherein said at least one pH-responsive
gelling polymer comprises acidic groups.
4. The composition of claim 3, wherein said pH-responsive gelling polymer
is a carboxy vinyl polymer of monomers selected from the group consisting
of acrylic acid, alkylacrylic acids, cycloalkylacrylic acids, arylacrylic
acids and alkylcrotonic acids.
5. The composition of claim 1, which exhibits a reversible increase in
viscosity in response to decreasing pH.
6. The composition of claim 5, wherein said pH-responsive gelling polymer
comprises basic groups.
7. The composition of claim 6, wherein said pH-responsive gelling polymer
is selected from the group consisting of amino derivatives of polyacrylate
and polyalkylacrylates.
8. The composition of claim 1, wherein said other polymer is a thermally
nonresponsive hydroxyalkyl cellulose.
9. The composition of claim 8, wherein said other polymer is
hydroxypropylmethylcellulose.
10. The composition of claim 2, wherein said pH-responsive gelling polymer
is polyacrylic acid and said other polymer is
hydroxypropylmethylcellulose.
11. The composition of claim 10, wherein said aqueous solution comprises
about 0.05-2.0% (w/w) polyacrylic acid and about 0.05-5.0% (w/w)
hydroxypropylmethylcellulose.
12. The composition of claim 11, wherein said aqueous solution comprises
about 0.3% (w/w) polyacrylic acid and about 1.5% (w/w)
hydroxypropylmethylcellulose.
13. The composition of claim 1, which further comprises a salt in an amount
effective to modify the viscosity of said aqueous solution.
14. The composition of claim 13, wherein said salt is present in a salt to
polymer ratio of about 0.001 to 0.5.
15. The composition of claim 1, which further comprises an effective amount
of a therapeutic or diagnostic agent.
16. A pharmaceutical composition that includes:
a) a pH-responsive reversibly gelling delivery vehicle comprising an
aqueous solution including about 0.01% to 10.0% (w/w) of at least one
pharmaceutically acceptable pH-responsive gelling polymer and about 0.01%
to 20.0% (w/w) of at least one other pharmaceutically acceptable thermally
nonresponsive polymer; and
b) an effective amount of a therapeutic or diagnostic agent.
17. A pharmaceutical composition as claimed in claim 16, wherein said
therapeutic or diagnostic agent is selected from the group consisting of
analgesics, anesthetics, antiarthritics, antiinflammatory substances,
antiasthmatics, antibacterials, anticoagulants, anticonvulsives,
antidepressants, antidiabetics, antifungals, antihistaminics and
decongestants, anti-hypertestive compounds, antiparasitics,
antipsychotics, antivirals, carbonic anhydrase inhibitors,
antineoplastics, immunosuppressive agents, miotics, anticholinergics,
muscle relaxants, mydriatics, nucleic acids and oligonucleotides,
ophthalmic agents, peptides and proteins, contrast agents, dyes,
fluorescent compounds, radiotracers and lubricating agents.
18. A pharmaceutical composition as claimed in claim 17, wherein said
therapeutic or diagnostic agent is an ophthalmic agent.
19. A pharmaceutical composition as claimed in claim 18, wherein said
ophthalmic agent is selected from the group consisting of anti-glaucoma
substances, dyes, fluorescent compounds, epinephrine, thereof,
hyperosmotic agents, lubricating agents, substances for determining
pupillary response, antibacterials, antifungals, antivirals,
anti-inflammatory agents, analgesics, nucleic acids, oligonucleotides,
peptides and proteins.
20. A pharmaceutical composition as claimed in claim 17, which is
formulated as an eye drop.
21. A method for sustained delivery of a therapeutic or diagnostic agent to
a patient, said method comprising administering to said patient a
pharmaceutical composition that includes an effective amount of said
therapeutic or diagnostic agent, disposed within a pH-responsive
reversibly gelling delivery vehicle comprising an aqueous solution
including about 0.01% to 10.0% (w/w) of at least one pharmaceutically
acceptable pH-responsive gelling polymer and about 0.01% to 20.0% (w/w) of
at least one other pharmaceutically acceptable thermally nonresponsive
polymer.
22. A method according to claim 21, wherein said pharmaceutical composition
is administered by a route selected from the group consisting of
ophthalmic, nasal, oral, otic, topical, rectal, vaginal and urinary tract.
Description
FIELD OF THE INVENTION
The present invention relates to compositions and methods for sustained
delivery of bio-affecting substances, such as diagnostic or therapeutic
agents. More particularly, the present invention is directed to
reversibly-gelling drug delivery vehicles comprising an aqueous solution
of polymers, at least one of which is transformed from a liquid to a gel
form in response to changes in pH.
BACKGROUND OF THE INVENTION
Various methods and compositions have been proposed for efficient delivery
of therapeutic and diagnostic agents to their sites of action. One
difficulty in the administration of such agents is the necessity for the
drugs to remain in contact with the target tissue for a sufficient period
of time, at a sufficient concentration to achieve the desired therapeutic
or diagnostic effect. Such difficulties are particularly pronounced for
compounds that must be administered by topical application, especially to
fluid-associated tissues such as ocular tissue, nasal mucosa or the oral
cavity. To illustrate, conventional ocular delivery systems such as eye
drops often result in low bioavailability and poor therapeutic response
because high tear fluid turnover and dynamics result in rapid precorneal
elimination of the compounds. An increase in dosing frequency or the use
of highly concentrated solutions to increase bioavailability is
undesirable due to poor patient compliance and/or the risk of toxicity
resulting from the systemic absorption of the drug via the nasolacrimal
duct. Similar difficulties are encountered in administration of topical
agents to other fluid-associated surface tissues, such as the nasal mucosa
or oral cavity.
To address the problems associated with ocular drug delivery, various
ophthalmic vehicles, such as suspension, ointments and inserts, have been
investigated in attempts to extend the ocular residence time of drugs for
topical applications to the eye. Such compositions have been applied
directly to the conjunctiva or cul-de-sac of the eye to facilitate
sustained retention of pharmaceutical agents contained therein on the
surface of the eye.
Although these ocular delivery systems offer some improvement over
conventional ophthalmic solutions, they have received poor patient
compliance as a result of eye irritation due to particulate matter in
suspensions, blurred vision caused by ointments, discomfort due to
crusting of gels and ointments around the eye and difficulties associated
with the placement and removal of inserts in the eye.
Another disadvantage of semi-solid gels or ointments is the tendency for
these compositions to migrate within the cul-de-sac or to be lost from the
eye. Additionally, such gels or ointments often persist in the ocular
environment past the point at which all of the pharmaceutical compound has
been delivered, thereby continuing to cause undesirable side effects such
as crusting of the material and blurred vision.
Thus, from the point of view of patient compliance, a liquid ocular
delivery system is most acceptable due to its ease of administration
compared to the semi-solid gels and ointments described above. However,
conventional liquid delivery systems are incapable of achieving the
extended surface contact for sustained delivery of the diagnostic or
therapeutic agent.
One approach to increasing the residence time of topically-applied drugs
while enabling administration of the drugs in liquid form has been to
develop delivery systems based on the concept of in situ gel formation.
These delivery systems are made from polymers that exhibit phase
transitions due to physico-chemical changes in their microenvironments.
They can be instilled as liquid drops into the cul-de-sac of the eye, for
example, where the microenvironment of the eye transforms the polymers
into a gel or semi-solid phase. Similarly, liquid forms of the delivery
systems can be introduced into the nasal mucosa, oral cavity or other
physiological environment, wherein they would transform into a gel.
Sustained release of ophthalmic drugs has been reported from gels and
polymer matrices, and improved bioavailability and patient response to
therapeutic agents has been shown in many cases. For example, Schoenwald
et al., J. Pharm. Sci., 67: 1280-1283 (1978), showed that aqueous
Carbopol.RTM. gels administered into rabbit eyes were retained for 4-6
hours and resulted in longer duration of action of incorporated
pilocarpine compared to a viscous solution preparation (see also U.S. Pat.
Nos. 4,271,143 and 4,407,792).
Subsequently, numerous in situ gel-forming delivery vehicles have been
disclosed, which are based in changes in physico-chemical structure as a
result of variations in temperature, pH, ionic strength, or a combination
thereof. In U.S. Pat. No. 4,188,373, for example, a gel-forming drug
delivery system is disclosed which utilizes proprietary non-ionic
difunctional polyoxyalkyene derivatives of propylene glycol (known as
Pluronic.RTM. polyols) as a thermally gelling polymer. The desired sol-gel
transition temperature is said to be obtained by appropriate adjustment of
the polymer concentration. Another thermally triggered system is disclosed
in U.S. Pat. No. 4,474,751 and 4,474,752, which disclose an aqueous drug
delivery system, based on proprietary non-ionic tetrafunctional
polyoxyalkylene derivatives of ethylene diamine (known as Tetronic.RTM.
polyols), which gel at temperatures from about 30.degree.-100.degree. C.
The sol-gel transition temperature and rigidity of these gels are said to
be capable of adjustment by changes in polymer concentration combined with
the pH and ionic strength of the solution. These compounds contain from
about 10% to about 50% by weight of Tetronic.RTM. polymers. Because of the
adjustments to the solutions that must be made in order to produce a
compound which sets at a physiologically useful temperature, the available
viscosity range of such gelled products is limited.
As an alternative, in situ gel-forming compositions have been developed
which gel in response to changes in pH. For example, U.S. Pat. No.
5,292,517 discloses a pH sensitive, reversible gelling copolymeric drug
delivery system, which comprises an aqueous solution containing up to 25%
(w/v) of poly (methylvinylether)/maleic acid) as the pH-sensitive gelling
copolymer. These compositions are said to exhibit a sol-gel transition
over physiologically compatible pH ranges.
Although successful in achieving increased drug retention times, the
relatively high polymer concentration utilized in such thermally- or
pH-sensitive gelling formulations undesirably increases the buffering
capacity and the thermal energy needed to induce gelation of those
formulations, leading to irritation and discomfort when used in the eye or
other physiological target tissue. Moreover, the use of such high polymer
concentrations is costly, and can retard the gelling process in situ,
which can result in loss of the pharmaceutical agent from the site of
administration during the lengthy time in which gelling occurs.
Addressing the difficulties associated with reversibly gelling compositions
containing high concentrations of the gelling polymer, U.S. Pat. No.
5,252,318 discloses a reversibly gelling composition having a lower
polymer concentration, which exhibits a sol-gel transition in response to
simultaneous variation in two physical parameters, such as temperature and
pH. The use of a combined polymer system that reversibly gels in response
to two or more physico-chemical parameters is said to enable the
formulation of in situ gelling compositions having a significantly reduced
polymer concentration. While the reduction in polymer concentration solves
the problems associated with high polymer concentration, the requirement
for a composition that gels in response to simultaneous variations in at
least two physical parameters limits the flexibility of formulating in
situ gel-forming compositions, inasmuch as they must contain at least one
pH-sensitive polymer and at least one thermally sensitive polymer.
Accordingly, a distinct advantage would be obtained by providing a
reversibly gelling drug delivery composition comprising an aqueous
solution of polymers at sufficiently low concentration to avoid the
undesirable effects of high buffering capacity and slow induction of
gelation, but which is not dependent on two independent physico-chemical
parameters to achieve that result. Such a composition would retain the
advantages of the two-parameter reversible gelling compositions described
above, but would also enable greater flexibility in formulating in situ
gelling compositions for delivery of a wide variety of diagnostic and
therapeutic agents.
SUMMARY OF THE INVENTION
The present invention provides a reversibly-gelling composition for
sustained delivery of therapeutic or diagnostic agents that can be
formulated at a low polymer concentration, yet relies on only one
physico-chemical parameter for its reversibly-gelling characteristic. The
composition, which exhibits the property of reversible gelation in
response to variation in pH over a pre-determined range, comprises an
aqueous solution that includes about 0.01% to 10.0% (w/w) of at least one
pharmaceutically acceptable pH-responsive gelling polymer and about 0.01%
to 30.0% (w/w) of at least one other pharmaceutically acceptable polymer.
Previously, it had been believed that a reversibly gelling composition
could not be produced with such a low concentration of polymers unless a
multiple gelation triggering mechanism (i.e., substantially simultaneous
changes in pH and temperature) were employed. In accordance with the
present invention, it was surprisingly discovered that superior
reversibly-gelling compositions can be formulated at low polymer
concentration using two or more compatible polymers, one of which is
sensitive to changes in pH, the others of which need not be sensitive to
changes in temperature.
According to one aspect of the invention, the above-described composition
exhibits a reversible change in viscosity in response to increasing pH.
The pH-sensitive gelling polymer of these compositions contains acidic
groups, and is preferably a polymer of acrylic acid or derivatives
thereof. According to another aspect of the invention, the above-described
compositions exhibit a reversible change in viscosity in response to
decreasing pH. The pH-sensitive gelling polymers of these compositions
contain basic groups, and preferably are polymers having weakly-pendant
amino groups. The second polymeric component of either the acidic or basic
gelling compositions of the invention comprises a pharmaceutically
acceptable water-soluble polymer that need not rely on changes in pH or
temperature for its contribution to the reversible gelation of the
composition and need not be capable of gelation on its own. This polymeric
component is compatible with the pH-responsive polymer, such that a clear
solution of the composition is obtained at pH of formation (i.e., low pH
for acidic compositions and high pH for basic compositions). In a
preferred embodiment, the polymer is a thermally insensitive hydroxyalkyl
cellulose.
According to another aspect of the invention, a pharmaceutical composition
is provided that includes a pH-sensitive reversibly gelling drug delivery
vehicle as described above and an effective amount of a therapeutic or
diagnostic agent. Additionally, methods are provided for sustained
delivery of a therapeutic or diagnostic agent to a patient. Such methods
comprise administering a pharmaceutical composition that includes an
effective amount of the therapeutic or diagnostic agent disposed within a
pH-sensitive reversibly gelling drug delivery vehicle as described above.
The reversible gel-forming properties of the compositions of the invention
make them well suited for sustained delivery of a wide variety of
therapeutic and diagnostic agents via topical application, particularly to
mucosa and other fluid-associated or physically inaccessible tissues such
as eyes, ears, the oral and nasal cavity and similar physiological
environments. Additionally, the gel-forming delivery vehicle and its
methods of use in accordance with the present invention offer a notable
advantage over in situ gel-forming drug delivery systems and methods of
the prior art. For instance, the reversible gelling compositions of the
invention contain comparatively low concentrations of polymeric
components, the lowered buffering capacity and thermal gelation threshold
obtained thereby resulting in rapid formation of superior gels in situ and
the minimization of patient discomfort resulting from exposure of tissues
to pH extremes for extended periods, the low polymer concentration also
reducing the cost of producing such compositions. Moreover, these
advantageous features are accomplished through a polymeric formulation,
the gelation of which is triggered by only one physico-chemical parameter
(i.e., change in pH). This feature of the compositions of the invention
enables a broad range of polymeric components to be utilized, thereby
enabling greater flexibility in the formulation of sustained release drug
delivery vehicles for a variety of applications.
Additional advantages and features of the present invention will be
apparent to those skilled in the art from the Detailed Description of the
Invention set forth below, considered in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. Shear stress vs. shear rate flow curves of 1.5%
hydroxypropylmethylcellulose (HPMC), 0.3% Carbopol aqueous solution at pH
4.0 and 7.4. The measurements at 25.degree. C. are represented by dashed
lines and that at 37.degree. C. by a solid line.
FIG. 2. Log viscosity vs. log shear rate profiles of 1.5% HPMC, 0.3%
Carbopol aqueous solution at pH 4.0 and 7.4. The measurements at
25.degree. C. are represented by dashed lines and that at 37.degree. C. by
a solid line.
FIG. 3. Shear stress vs. shear rate flow curves of aqueous polymer
solutions containing 0.3% Carbopol with varying concentrations of HPMC.
Curve A, B, and C represent 2.0%, 1.5%, and 1.0% HPMC concentrations,
respectively. Solid lines represent samples at pH 7.4 and 37.degree. C.,
and the dashed lines represent samples at 4.0 and 25.degree. C.
FIG. 4. Shear stress vs. shear rate flow curves of aqueous polymer
solutions containing 1.5% HPMC with varying concentrations of Carbopol.
Curve A, B, and C represent 0.4%, 0.3%, and 0.2% Carbopol concentrations,
respectively.
FIG. 5. Flow curves of 1.5% HPMC, 0.3% Carbopol aqueous solutions prepared
using HPMC of three different average molecular weights. The alphabets A,
B, and C represent HPMC average molecular weights of 246 kDa, 86 kDa, and
26 kDa, respectively. The curves followed by alphabets with a prime (A',
B', and C') represent samples at pH 4.0 and 25.degree. C., and those with
alphabets without the prime (A, B, and C) represent samples at pH 7.4 and
37.degree. C.
FIG. 6. Effect of change in HPMC concentration on the rate of TM release
from gels containing 0.1% TM at pH 7.4. The release profile from gel
containing 0.3% Carbopol with 2.0% HPMC (circles), 1.5% HPMC (closed
squares), and 1.0% HPMC (open).
FIG. 7. Effect of change of Carbopol concentration on the rate of TM
release from gels containing 0.1% TM at pH 7.4. The release profile from
gel containing 1.5% HPMC with 0.4% Carbopol (circles), 0.3% Carbopol
(closed squares), and 0.2% Carbopol (open squares).
FIG. 8. Effect of change in average molecular weight of HPMC on the rate of
TM release from gels containing 0.1% TM at pH 7.4. The release profile
from gel containing 0.3% Carbopol, and 1.5% HPMC of average molecular
weights of 246 kDa (circles, 86 kDa (closed squares), and 26 kDa (open
squares).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a pH-responsive reversibly gelling
composition for sustained delivery of therapeutic or diagnostic agents,
and uses thereof in formulation and administration of pharmaceutical
compositions containing such therapeutic or diagnostic agents. These
compositions exhibit a sol-gel transition over physiologically compatible
pH ranges. In the liquid form, the compositions are composed of a clear,
free-flowing physiologically compatible solution. Upon exposure to a
pre-determined variation in pH, the compositions rapidly increase in
viscosity by over an order of magnitude to a highly viscous gel-like
consistency, which is optically clear, lubricating and slowly-dissolving.
These properties make the reversibly gelling compositions of the invention
suitable for use as drop- or spray-instillable or topical drug delivery
vehicles. The compositions are particularly suitable for delivering
pharmaceutical compounds to the ocular environment due to the clarity and
lubricating properties of the gel.
The compositions of the invention are unique from those disclosed in the
prior art in that they possess the above-described clarity and rapid
gelation response to changes in pH, yet contain very small polymer
concentrations, as compared with pH-sensitive reversible gelation systems
heretofore available. Although reversibly gelling compositions of low
polymer concentration have been disclosed, (U.S. Pat. No. 5,252,318) it
has been taught that a composition having the desirable gelling properties
described hereinabove required the use of two or more polymers, one of
which exhibits thermally-responsive gelation, while the other polymer
exhibits pH-responsive gelation. In accordance with the present invention,
and contrary to the teachings of the prior art, it has now been discovered
that a low-concentration reversibly-gelling compositions can be formulated
without the requirement for inclusion of a temperature-sensitive gelling
polymer. Thus, compositions may be formulated which exhibit reversible
gelation in response to variations in pH only, yet the polymer
concentrations can be kept very low. Such compositions retain the
advantage of being lower in cost, having a substantially reduced buffering
capacity and rapid gelation at the sol-gel transition, and possess the
added advantage of enabling an additional range of polymers (i.e.,
thermally nonresponsive polymers) to be employed in formulating sustained
delivery pharmaceutical compositions.
An example of a reversibly-gelling composition of the invention which
exhibits an increase in viscosity in response to variation in pH over a
pre-determined range comprises an aqueous solution that includes a stable
combination of at least one pharmaceutically acceptable pH-responsive
gelling polymer and at least one other pharmaceutically acceptable,
thermally nonresponsive polymer in amounts sufficient to produce the
reversible change in pH over the pre-determined pH range. As used herein
with reference to the components of the gel-forming composition and
pharmaceutical formulations of the invention, the expression
"pharmaceutically acceptable" refers to substances which do not adversely
affect the activity or efficacy of the therapeutic or diagnostic agent or
agents included in the reversibly gelling delivery composition, and which
are not in themselves toxic to the recipient. With reference to the
polymers comprising the gel-forming composition of the invention, the
expression "pH-responsive" refers to polymers which exhibit the property
of reversible gelation in response to a change, either an increase or a
decrease, in pH over a pre-determined range. Similarly, the expressions
"thermally responsive/non-responsive" refers to polymers which do/do not
exhibit the property of gelation in response to a change in temperature,
although, as will be appreciated by those skilled in the art, other
characteristics of a gelatinous composition may be affected or modified by
temperature.
Preferred exemplary compositions of the invention undergo an increase in
viscosity in response to increasing pH over a pre-determined range,
preferably in a physiological range between about pH 2.5 and pH 7.5.
Depending on polymer type, polymer concentration, temperature, ionic
strength, shear rate and similar factors, the change in viscosity will
range from about 200 cP to about 1,000,000 cP in response to variation
between about 2.5 and 7.5. Preferred pH-responsive gelling polymers
exhibiting increased viscosity in response to increasing pH include, but
are not limited to: linear, branched or cross-linked acidic polymers,
especially carboxylic acid-containing polymers, and particularly
carboxyvinyl polymers of monomers of acrylic acid and alkyl or cycloalkyl
acrylic acids such as methacrylic acid, ethacrylic acid,
.beta.-methacrylic acid and .alpha.-cyclohexacyclic acid; as well as
arylacrylic acids such as .alpha.-phenylacrylic acid and
.alpha.-benzylacrylic acid. and alkylcrotonic acids such as
cis-.alpha.-methylcrotonic acid, trans-.alpha.-methylcrotonic acid,
.alpha.-butylcrotonic acid, and the like. These pH-sensitive polyacids are
incorporated into compositions of the invention at a concentration of
between 0.01% to 10.0% (w/w), with preferred concentrations of 0.05% to
2.0% (w/w).
Other exemplary compositions of the invention undergo an increase in
viscosity in response to decreasing pH over a pre-determined range.
Preferred pH-responsive gelling polymers that increase viscosity with
decreasing pH include, but are not limited to: linear, branched, or
cross-linked basic polymers, including amino derivatives of polyacrylate
and polyalkylacrylates, such as poly-N-N-dimethylaminoethylmethacrylate,
and other polymers containing weakly basic pendant groups. These polymers
are incorporated into compositions of the invention at a concentration of
0.01% to 10.0% (w/w), and preferably from 0.05% to 2.0% (w/w).
Compositions of the invention containing such pH-responsive polymers
exhibit an increase in viscosity from about 200 cP to 1,000,000 cP in
response to variations in pH ranging from about pH 9.0 to pH 6.0.
To achieve the desired gelation properties at low polymer concentration,
compositions of the invention comprise at least one other pharmaceutically
acceptable polymer that is capable of combining or admixing with the
pH-responsive polymers to impart the desired rheological properties to the
compositions of the invention in both the soluble form and the gel-like
form. Preferred polymers for use in this capacity include, but are not
limited to, various thermally nonresponsive cellulose derivatives, such as
certain alkyl celluloses, hydroxyalkyl celluloses and cellulosic ethers.
Particularly preferred is hydroxypropylmethylcellulose (HPMC) at a
concentration of about 0.01% to 20.0% (w/w), with 0.05% to 5.0% (w/w)
being particularly preferred. Thermally responsive cellulose derivatives
have previously been disclosed to be synergistic in gel formation with
certain of the pH-responsive polymers described above, a feature which
previously was thought to be primarily associated with the temperature
sensitivity of these polymers. However, in accordance with the present
invention, it has been discovered that thermally nonresponsive cellulose
derivatives, particularly HPMC, also exhibit the same synergism, inasmuch
as mixtures of such polymers and the pH-responsive polymers in accordance
with the invention exhibit viscosities substantially greater than the sum
of the individual viscosities of the individual aqueous polymer solutions.
This unique feature of thermally non-responsive cellulose derivatives,
along with their visco-elastic stability over a wide range of pH from
approximately 3 to 11 makes them particularly suitable as the additional
polymeric component of the compositions of the invention.
A preferred exemplary composition of the invention thus comprises a
homogenous association of hydroxypropylmethylcellulose and a cross-linked
polyacrylic acid, such as Carbopol 974P NF, a hydrophilic acrylic polymer
available from the B. F. Goodrich Company. These polymers are preferably
incorporated into an aqueous solution at concentrations ranging from 0.01%
to 10.0% (w/w) Carbopol and from 0.01% to 20.0% (w/w) HPMC, preferably
with Carbopol concentrations of 0.05% to 2.0% and HPMC concentrations of
0.05% to 5.0%, and most preferably at a Carbopol concentration of 0.3% and
an HPMC concentration of 1.5%. It will be appreciated by those of skill in
the art that varying the concentration ranges of the preferred composition
results in a wide variety of viscosities and sol-gel transition pHs.
The compositions of the invention can be formulated at a variety of pHs,
and it is contemplated that such formulations may include pHs at which the
compositions are in flowable liquid form, or pHs at which the compositions
are in gel form. The flowable liquid forms of the composition are
particularly useful for pharmaceutical formulations to be applied by drops
(e.g., eye drops) or sprays (e.g., nasal sprays), and the like, while the
gel form of the composition are suitable for topical administration of
pharmaceutical compounds, such as administration on the surface of the
skin.
The osmolality of the compositions of the invention may be adjusted to suit
the physiological environment into which the composition is to be
introduced. The osmolality can be adjusted through the addition of
physiologically acceptable salts or non-ionic supplements, including
sodium chloride, potassium chloride, magnesium chloride, sodium lactate,
magnesium phosphate, mannitol, sucrose, glycerine, and the like.
Additionally, if desired, the compositions of the invention may also
contain other preservatives or additives. Suitable water-soluble
preservatives include sodium bisulfite, sodium thiosulfate, ascorbate,
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric, borate,
parabens, benzylalcohol and phenylethanol. These agents may be present,
generally, in amounts of about 0.001% to about 5% by weight and,
preferably, in the amount of about 0.01 to about 2%.
In addition to being useful for adjusting osmolality, the viscosity of the
aqueous compositions of the invention can be modified by the addition of a
pharmaceutically acceptable salt, such as a mono- or divalent salt,
including sodium chloride, potassium chloride, calcium chloride, or
mixtures thereof, as well as suitable alkali metal salts such as sodium
sulfate. The ratio of salt to combined polymer in the solution should
range from 0 to about 0.5, and preferably from about 0.045 to 0.075. The
addition of salt tends to lower the viscosity of the aqueous polymer
composition and thus can be used for fine adjustments of viscosity in the
formulation of various pharmaceutical compositions.
The pH-responsive reversibly gelling compositions of the invention may be
utilized as wetting agents or lubricants without the addition of a
therapeutic or diagnostic agent. However, it is contemplated that the more
significant utility of the compositions of the invention will be as
sustained delivery vehicles for administering therapeutic or diagnostic
compounds.
The drug delivery pharmaceutical compositions of the invention may be
formulated as aqueous solutions or as gels, and are therefore suitable for
utilization in a wide variety of physiological applications, such as
ocular, oral, otic, nasal, topical (epidermal), rectal, vaginal or
intraurinary administration of pharmaceutical compounds. Accordingly, a
pharmaceutical composition of the invention will contain, based on the
total weight of the composition, and effective amount of one or more
therapeutic or diagnostic agents, typically from about 0.0001% to 50% by
weight therapeutic or diagnostic agent. Depending upon the condition of
the patient, the above-stated amounts may be varied to increase or
decrease the dosage schedule, as appropriate. As used herein, the term
"therapeutic agent" refers to a substance used in treating or ameliorating
a disease or a medical condition. The term "diagnostic agent" refers to a
substance used in diagnosing the nature of a disease or medical condition,
or some aspect thereof. The term "patient" refers to the subject having
the disease or medical condition being treated or diagnosed, and is
intended to include humans and animals.
Virtually any therapeutic agent or diagnostic agent capable of
administration using the various in situ gelling compositions of the prior
art can be administered using the sustained-release compositions of the
present invention. Particularly preferred are therapeutic and diagnostic
agents which exhibit poor bioavailability, including timolol, betaxalol,
levobunolol, pilocarpine, dipivefrin, and the like. Other therapeutic and
diagnostic agents that can be administered by the sustained-delivery
compositions of the present invention include, but are not limited to:
(1) analgesics such as aspirin, acetaminophen, diflusinal and the like;
(2) antibacterial substances such as beta-lactam antibiotics, including
cefoxitin, n-formamidoyl-thienamycin and other thienamycin derivatives,
tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin,
penicillin G, polymyxin B, vancomycin, cefazolin, cephaloridine,
chibrorifamycin, gramicidin, bacitracin, sulfonamides; aminoglycoside
antibiotics such as gentamycin, kanamycin, amikacin, sisomicin and
tobramycin; nalidixic acid and analogs such as norfloxacin and the
antimicrobial combination of flucalanine/pentizodone; nitrofurazones, and
the like;
(3) antihistaminics and decongestants such as pyrilamine, chlorpheniramine,
tetrahydrazoline, antazonline, and the like;
(4) antiathsma drugs such as theophylline, ephedrine, beclomethasone
diproprionate, epinephrine and the like;
(5) anti-inflammatories and anti-arthritics such as cortisone,
hydrocortisone, hydrocortisone acetate, betamethasone, dexamethasone,
dexamethasone sodium phosphate, preunisone, methylpredinisolone,
medrysone, fluorometholone, fluocortolone, preunisolone, preunisolone
sodium phosphate, triamcinolone, phenylbutazone, ibuprofen, indomethacin,
sulindac, its salts and its corresponding sulfide, and the like;
(6) miotics and anticholinergics such as echothiophate, pilocarpine,
physostigmine salicylate, diisopropylfluorophosphate, epinephrine,
dipivolyl epinephraine, neostigmine, echothiophate iodide, demecarium
bromide, carbachol, methacholine, bethanechol, and the like;
(7) mydriatics such as atropine, homatropine, scopolamine,
hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine,
cyclopentolate, oxyphenonium, eucatropine, and the like; and other
medicaments used in the treatment of eye conditions or diseases, such as
(9) antiglaucoma drugs, for example, betaxalol, pilocarpine, timolol,
especially as the maleate salt and R-timolol and a combination of timolol
or R-timolol with pilocarpine, as well as epinephrine and epinephrine
complex or prodrugs such as the bitartrate, borate, hydrochloride and
dipivefrin derivatives and hyperosmotic agents such as glycerol, mannitol
and urea;
(10) antiparasitic compounds and/or anti-protozoal compounds such as
ivermectin; pyrimethamine, trisulfapyrimidine, clindamycin and
corticosteroid preparations;
(11) antiviral effective compounds such as acyclovir,
5-lodo-2'-deoxyuridine (IDU), adenosine arabinoside (Ara-A),
trifluorothymidine and interferon and interferon inducing agents such as
Poly I:C;
(12) urinary tract disinfectives such as sulfamethoxyazole, trimethoprim,
nitrofurantoin, norfloxacin and the like;
(13) anticoagulants such as heparin, bishydroxy coumarin, warfarin and the
like;
(14) anticonvulsants such as diphenylhydantoin, diazepan and the like;
(15) antidepressants such as amitriptyline, chlordiazepoxide, perphenazine,
protriptyline, imipramine, doxepin and the like;
(16) antidiabetics such as insulin, tolbutamide, somatostatin and its
analogs, tolazanide, acetohexamide, chlorpropamide and the like;
(17) antipsychotics such as prochlorperazine, lithium carbonate, lithium
citrate, thioridazine, molindone, fluphenazine, trifluoperazine,
perphenazine, amitriptyline, triflupromazine and the like;
(18) antihypertensives such as spironolactone, methyldopa, hydralazine,
clonidine, chlorothiazide, deserpidine, timolol, propranolol, metopropol,
prazosin hydrochloride, reserpine and the like;
(19) muscle relaxants such as succinylcholine chloride, danbrolene,
cyclobenzaprine, methocarbomol, diazepam and the like;
(20) carbonic anhydrase inhibitors such as acetazotamide, dichlorphenamide,
2-(p-hydroxyphenyl)thio-5-thio-phenesulfonamide,
6-hydroxy-2-benzothiazolesulfonamide and
6-pivaloyloxy-2-benzothiazolesulfonamide;
(21) anti-fungal agents such as amphotericin B, nystatin, flucytosine,
natamycin, and miconazole;
(22) anesthetic agents such as etidocaine cocaine, henoxinate, dibucaine
hydrochloride, dyclonine hydrochloride, naepaine, phenacaine
hydrochloride, piperocaine, proparacaine hydrochloride, tetracaine
hydrochloride, hexylcaine, bupivacaine, lidocaine, mepivacaine and
prilocaine;
(23) ophthalmic diagnostic agents such as
(a) those used to examine the retina and chloride-sodium fluorescein;
(b) those used to examine the conjunctive, cornea and lacrimal apparatus
such as fluorescein and rose bengal; and
(c) those used to examine abnormal pupillary responses such as
methacholine, cocaine, adrenaline, atropine, hydroxyamphetamine and
pilocarpine;
(24) ophthalmic agents used as adjuncts in surgery such as
alphachymotrypsin and hyaluronidase;
(25) chelating agents such as ethylenediamine tetraacetate (EDTA) and
deferoxamine;
(26) immunosuppressive agents, antineoplastics and anti-metabolites such as
adriamycin, fluorouracil, asparaginase, methotrexate, cyclophosphamide,
6-mercaptopurine, azathioprine and the like;
(27) peptides and proteins such as atrial natriuretic factor,
calcitonin-gene related factor, lutinizing hormone, releasing hormone,
neuroterisin, vasoactive intestinal peptide, vasopressin, cyclosporine,
interferon, substance P enkephalins, epidermal growth factor, eye derived
growth factor, fibronectin, insulin-like growth factor and mesodermal
growth factor;
(28) nucleic acids, such as oligonucleotides, DNA fragments and the like;
and
(29) lubricating agents such as sodium hyaluronate or polyvinyl alcohol;
(30) combinations of the above such as antibiotic/anti-inflammatory as in
neomycin sulfate-dexamethasone sodium phosphate, concomittant
anti-glaucoma therapy such as timolol/maleate-aceclidine.
Representative diagnostic agents that may be incorporated in the drug
delivery vehicle of the present invention include contrast agents, dyes
and radiotracers, as well as biological molecules, such as antibodies,
oligonucleotides and various ligands, alone or conjugated to detectable
substances such as fluorescent compounds, dyes and enzymes.
The foregoing list of suitable bio-affecting agents is exemplary only and
is not intended to limit the scope of the present invention. Additionally,
it is also contemplated as being within the scope of the invention to
incorporate insoluble or erodible microparticulate drug delivery systems
known in the art into the compositions of the invention. Controlled
release drug delivery systems can thus be incorporated into the
compositions of the invention and retained at the site of administration
for particularly effective bioavailability and sustained release.
Gelation of pharmaceutical compositions of the invention will cause the
therapeutic or diagnostic agents included therein to become incorporated
into the gelled polymer matrix, which will remain at the site of
administration for sustained bioavailability and delivery as the gel
slowly erodes and the therapeutic or diagnostic agents diffuse into the
surrounding physiological environment. Along these lines it will be
appreciated by those skilled in the art that varying the concentration of
pharmaceutical agents within the composition will enable modification and
control of the quantity of pharmaceutical compound delivered by dropable
application, spray or topical administration. For example, a liquid drug
delivery vehicle can be prepared in accordance with the present invention
containing from about 0.0001 to about 50%, preferably about 0.01% to 20.0%
by weight of a therapeutic agent, as previously noted. For drop
instillation, the drop size will preferably range from approximately 20
.mu.l to 50 .mu.l with 25 .mu.l drops being particularly preferred.
Accordingly, one drop of the liquid composition, which comprises about 25
.mu.l of solution, would preferably contain approximately 0.0025 mg to
approximately 1.25 mg of pharmaceutical agent. Such an aqueous liquid drug
delivery vehicle can easily be modified for administration as an atomized
spray or vapor. de
The following examples are provided to describe the invention in further
detail. These examples are intended merely to illustrate specific
embodiments of the reversibly-gelling compositions of the invention and
should in no way be construed as limiting the invention.
EXAMPLE 1
Preparation of Reversibly-Gelling Drug Delivery Compositions and
Determination of Rheological Properties
MATERIALS AND METHODS
Polyacrylic acid is available as Carbopol.RTM. (974P NF) from B. F.
Goodrich, Cleveland, Ohio. Hydroxypropyl methylcellulose (HPMC) of three
different average molecular weight grades (MW=26 kDa; MW=86 kDa; and
MW=246 kDa) is available from the Dow Chemical Company, Midland, Mich.
Unless otherwise specified HPMC of MW=86 kDa was used in the preparation
of polymer solutions. Sodium hydroxide was purchased from J. T. Baker.
Aqueous solutions of 4.0% w/w HPMC were prepared by gradually adding
weighed quantities polymer to 1/3rd of the required distilled, deionized
water preheated to 90.degree. C., with constant stirring. The final volume
was made up by adding water cooled to 5.degree. C. 1.0% w/w Carbopol
solutions were prepared by dispersing the required amount in distilled,
deionized water. All experiments were carried out using the same batch of
prepared solutions. Solutions containing both HPMC and Carbopol were
prepared by adding appropriately weighed amounts of the 4.0% HPMC and 1.0%
Carbopol solutions. The resulting solutions were thoroughly mixed and
equilibrated. The pH of the same were then adjusted to either 4.0.+-.0.1
or 7.4.+-.0.2 by addition of measured volumes of a 0.5M sodium hydroxide
solution based on a titration curve for Carbopol. Finally, the desired w/w
% concentrations were made by adding required volumes of distilled,
deionized water to the samples. The samples were allowed to equilibrate
for 48 hrs at room temperature prior to the evaluation of their
rheological properties.
The rheological studies of the samples were carried out on a Haake
viscometer (RV20, CV20, RC20) using a cone (4.degree.) and plate geometry.
The temperature was maintained to within .+-.0.1.degree. C. by a Haake
recirculating bath connected to the viscometer. The viscosity (.eta.) and
shear stress (.tau.) of the polymer solutions of different compositions
were measured as a function of shear rate (D) at 25.degree. C. and
37.degree. C. A typical run comprised a shear rate change from 0 to 0.5
s.sup.-1 at a shear rate ramp speed of 0.05 s.sup.-1 /min, a 0.1 min wait
at 0.5 s.sup.-1, and finally a shear rate decrease to O s.sup.-1 at the
same ramp speed. The samples were equilibrated at the run temperature on
the plate for 5 minutes prior to the analysis.
RESULTS
Aqueous solutions of different compositions containing HPMC and Carbopol
were prepared and their rheological properties were studied. FIG. 1 shows
the shear stress vs. shear rate (.tau. vs. D) flow curves for aqueous
solutions containing 1.5% HPMC and 0.3% Carbopol at different conditions
of pH and temperature. All solutions demonstrate a pseudoplastic .tau. vs.
D flow curve with a yield point, indicating a plastic behavior. The
solution at pH 4.0 and 25.degree. C. has low shear stress and yield point.
Upon increasing the pH to 7.4, there is significant increase in the shear
stress and yield point value. An increase in temperature from 25.degree.
to 37.degree. C. along with the increase in pH does not affect yield point
and shear stress.
FIG. 2 is a plot of log viscosity vs. log shear rate (log.eta. vs. logD)
for the 1.5% HPMC, 0.3% Carbopol aqueous solutions under the same
conditions of pH and temperature as in FIG. 1. The solution at pH 4.0 and
25.degree. C. shows low viscosity. On increasing the pH from 4.0 to 7.4,
the solution transforms from a sol to a stiff gel. Both the solutions at
pH 7.4, one maintained at 25.degree. C. and the other at 37.degree. C.,
demonstrate log.eta. vs. logD profiles that are much higher in magnitude
than the solution at pH 4.0 and 25.degree. C. For purposes of comparison,
log.eta. vs. logD and .tau. vs. D plots, respectively, were generated for
a temperature/pH-triggered aqueous gelling system containing 1.5% methyl
cellulose (MC; Sigma Chemical Co., St. Louis, Mo.) and 0.3% Carbopol,
prepared by the same method as described for HPMC-Carbopol. Compared to
the HPMC-Carbopol Carbopol system shown in FIGS. 1 and 2, the MC-Carbopol
system showed a similar increase in viscosity, shear stress and yield
point values as the pH is increased from 4.0 to 7.4. However, unlike the
HPMC-Carbopol system, a simultaneous increase in temperature from
25.degree. to 37.degree. C. along with the pH change results in a further
increment in the values of viscosity, shear stress, and yield point.
However, these temperature mediated rheological changes in the MC-Carbopol
system were temporary and were seen only at low shear rates. As the shear
rate was increased, it was seen that the log.eta. vs. logD curve and the
.tau. vs. D flow curve of the solution at pH 7.4 and 37.degree. C.
approached and ultimately coincided with that of the solution at pH 7.4
and 25.degree. C. Following instillation of an ophthalmic delivery system
prepared using the MC-Carbopol system in the cul-de-sac of the eye, it is
likely to encounter shear forces at rates higher than 0.5 s.sup.-1
examined in the experiment. Thus, it appears that the in situ gelation of
the delivery system will occur as a result of the pH effect with little or
no contribution of the temperature related phase transition observed in
the in vitro experiments.
These rheological properties of the Carbopol-HPMC aqueous system are
indicative of its utility as an in situ gel forming delivery system for
ophthalmic and other applications. The delivery system can be formulated
to be a liquid at a specific pH which can be instilled into the eyes as
drops. Exposure to the physiological pH will induce a sol to gel phase
transition to form a semisolid gel in sit.
A detailed study on the effects of changing the solution composition on the
rheological properties was carried out. FIG. 3 shows the .tau. vs. D flow
curves for solutions containing 0.3% Carbopol with varying HPMC
concentrations. Higher .tau. responses and yield point values are observed
with increasing HPMC concentrations, both at pH 4.0 and 25.degree. C. and
at pH 7.4 and 37.degree. C. FIG. 4 shows the .tau. vs. D flow curves for
solutions containing 1.5% HPMC with varying Carbopol concentrations. A
similar trend of increase in the .tau. responses and yield point values is
seen with increase in Carbopol concentrations in the concentration range
examined. FIG. 5 shows the effect of changes in the average molecular
weight of HPMC used to prepare the 1.5% HPMC, 0.3% Carbopol solutions on
the .tau. vs. D flow curves. An increase in the average molecular weight
of HPMC used in the solution results in an increase in the observed .tau.
response and yield stress. These studies demonstrate that solutions of
desirable rheological properties can be prepared by appropriately choosing
the concentrations and/or molecular weights of the polymers. Ideally, an
in situ gelling delivery system should be a low viscosity, free flowing
liquid to allow reproducible administration into the eye as drops, and the
gel formed following phase transition should be strong enough to withstand
the shear forces in the cul-de-sac and demonstrate long residence times in
the eye or in other physiological environments.
The flow properties of any given system can have, in theory, a significant
effect on the behavior of that system when instilled into the eye or
applied to similar physiological environments. The gels formed by phase
transitions of aqueous solutions containing HPMC and Carbopol at
concentrations of 1.5% and 0.3%, respectively, and higher, have
demonstrated high .tau. response and yield point values, representing
strong three dimensional gel networks. These gels have adequate strength
to withstand the low shear forces likely to be encountered in the
cul-de-sac of the eye. These gels will not be susceptible to drainage from
the eye as seen in the case of ophthalmic solutions, and will have long
residence times.
EXAMPLE 2
Release Profile of Timolol Maleate from an Exemplary Reversibly-Gelling
Drug Delivery Composition
MATERIALS AND METHODS
Timolol maleate (TM) was purchased from Sigma Chemical Co. (St. Louis).
Timolol maleate was added to gels containing HPMC and Carbopol of
different compositions such that the final concentration of timolol
maleate was 0.1% w/w. Timolol maleate was gently mixed in gels (pH 7.4)
and allowed to equilibrate for 24 hours. Flow curves of TM containing gels
were compared with those without TM to ensure that the presence of drug at
concentrations of 0.1% did not affect the rheological properties of the
gels. Different gel samples containing 0.1% TM were filled in small,
circular plastic containers (14 mm inner diameter and 8 mm in depth) and
were allowed to gel in an incubator at 37.degree. C. for 30 minutes. Care
was taken that the gel contained no air bubbles and that the surface was
smooth. The containers were then introduced into 30.0 ml distilled,
deionized water in a jacketed beaker maintained at 37.degree. C. using a
circulating water bath. The release medium was stirred using magnetic stir
bars in such a way that the gel surface was not perturbed. Aliquots of 1
ml were withdrawn from the release medium at 0, 1, 3, 7, 11, 15, 19 and 24
hrs, and replaced with 1 ml water each time. At the end of 24 hrs, the
contents of the container were thoroughly mixed with the medium until all
the remaining polymeric gel were dissolved and a final aliquot was taken.
The aliquots were filtered through 0.2 .mu.m syringe filters and subjected
to HPLC analysis to determine the TM concentrations. The dilution of the
release medium due to replenishment following each aliquot withdrawal was
taken into account to calculate the fractional release of TM from the
gels.
HPLC Analysis of TM
The method of Podder et al., Exp. Eye Res., 54: 747-757 (1992), was used to
assay TM using a Shimadzu HPLC system, which consisted of a solvent
delivery module (model LC-600), an auto-injector (SIL-9A), a variable
wavelength detector (model SPD-6AV), and an integrator (model CR 501
Chromatopac). Aqueous samples of TM were analyzed on a Sulpelcosil LC-18
(octadecylsilane; 5-.mu.m particle packing; 250 mm.times.4.6 mm I.D.)
reversed-phase column using injection volumes of 25 .mu.l . The mobile
phase comprised 40% acetonitrile, 25% solution containing 4% triethylamine
(pH 3), and 35% water. The flow rate was 1 ml/min and the detector was set
at a wavelength of 294 nm. All analyses were done at ambient temperature
with helium-sparged mobile phases. The assay was sensitive to at least
0.625 .mu.g of TM.
RESULTS
Experiments were carried out to study the in vitro release profiles of TM
from the gels at pH 7.4 and 37.degree. C. FIGS. 6 and 7 compare the
fraction TM released from gel containing varying concentrations of HPMC
and Carbopol. Focusing first on the exemplary composition of 1.5% HPMC,
0.3% Carbopol (closed squares), the release from the gel is slow and
approximately 60% of the total incorporated drug was released during the
duration of the study (24 hrs). This demonstrates that the gels have a
capacity to release TM in a sustained manner. Periodic visual inspection
of the gels in the containers showed that the gels underwent gradual
dissolution into the surrounding medium, and that the rate of dissolution
decreased as the concentration or the molecular weights of the polymers
comprising the gels increased. A similar drug release rate and pattern of
dissolution was observed in comparative testing of a
temperature/pH-triggered aqueous gelation system comprising 0.3% Carbopol
and 1.5% MC. The residence time of the in situ formed gel in the
cul-de-sac of the eye is anticipated to be approximately 4-6 hrs, during
which time most of the drug will be retained in the gels and the gradual
release will occur largely due to the dissolution of the polymeric gels
compared to the diffusional release.
The effect of changing the composition of the polymer solution on the
release of incorporated TM was also studied. FIG. 6 shows the release
profiles of TM from gels containing 0.3% Carbopol with varying HPMC
concentrations. A decrease in the rate of release of TM was seen with
increasing HPMC concentration. FIG. 7 shows the fraction TM released over
time from gels containing 1.5% HPMC with varying Carbopol concentrations.
Slight decrease in the rate of release of TM from the gels is observed
with increasing Carbopol concentrations. Finally, the effect of changing
the molecular weight of HPMC while keeping the total polymer concentration
the same is shown in FIG. 8. An increase in the average molecular weight
of the HPMC substantially decreased the rate of TM release. The data
suggests that considerable changes in the release rate of incorporated
drugs can be achieved by changing the composition of the delivery system.
While certain embodiments of the present invention have been described
and/or exemplified above, various other embodiments will be apparent to
those skilled in the art from the foregoing disclosure. The present
invention is, therefore, not limited to the particular embodiments
described and/or exemplified, but is capable of considerable variation and
modification without departure from the scope of the amended claims.
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